Systematic review reveals efficacy of siRNA therapy in neurodegenerative diseases, highlighting gene silencing and delivery challenges.
Neurodegenerative diseases (NDDs) pose a significant global health challenge, causing progressive neuronal loss and debilitating impairments. While current treatments offer only symptomatic relief, small interfering RNAs (siRNAs) have emerged as a promising therapeutic modality. This systematic review analyzed the literature (2000-2025) from different databases on siRNA therapy for NDDs, focusing on mechanisms, delivery approaches, therapeutic efficacy, and safety profiles to provide an integrated, evidence-based synthesis. The siRNA precise sequence specificity allows them to silence disease-related genes, addressing the root causes of these disorders. This review examines the fundamental biology of siRNAs, including advancements in their design, chemical modification, and innovative strategies to overcome the blood–brain barrier (BBB) for central nervous system delivery. We detail siRNA-based therapeutic strategies for major NDDs – Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis – highlighting the transition from preclinical successes to clinical trials. Despite challenges in delivery and immunogenicity, the precision of siRNA-mediated gene silencing positions this technology at the forefront of efforts to develop disease-modifying treatments, paving the way for a new era of personalized neurotherapeutics.
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